Therapeutic Drug Monitoring Of Antibiotics Research Articles

[Translated article] Therapeutic Drug Monitoring of antibiotic and antifungical drugs in paediatric and newborn patients. Consensus Guidelines of the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Paediatric Infectious Diseases (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic (PK/PD) parameters is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised paediatric host.In neonates and children, infections account for a high percentage of hospital admissions, and anti-infectives are the most used drugs. However, paediatric PK/PD studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals—usually used off-label in paediatrics—to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the PK parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, paediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly by the Spanish Society of Hospital Pharmacy and the Spanish Society of Paediatric Infectious Diseases, is to describe the available evidence on the indications for therapeutic drug monitoring (TDM) of antibiotics and antifungals in newborn and paediatric patients, and to provide practical recommendations for TDM in routine clinical practice to optimise their dosing, efficacy and safety. Of antibiotics and antifungals in the paediatric population.

Documento nacional de consenso de monitorización terapéutica de antibióticos y antifúngicos en el paciente pediátrico y neonatal de la Sociedad Española de Farmacia Hospitalaria (SEFH) y la Sociedad Española de Infectología Pediátrica (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic param- eters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host.In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treat- ment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide prac- tical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.

Documento nacional de consenso de monitorización terapéutica de antibióticos y antifúngicos en el paciente pediátrico y neonatal de la Sociedad Española de Farmacia Hospitalaria (SEFH) y la Sociedad Española de Infectología Pediátrica (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic parameters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host.In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide practical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.

The clinical application of beta-lactam antibiotic therapeutic drug monitoring in the critical care setting.

Critically ill patients have increased variability in beta-lactam antibiotic (beta-lactam) exposure due to alterations in their volume of distribution and elimination. Therapeutic drug monitoring (TDM) of beta-lactams, as a dose optimization and individualization tool, has been recommended to overcome this variability in exposure. Despite its potential benefit, only a few centres worldwide perform beta-lactam TDM. An important reason for the low uptake is that the evidence for clinical benefits of beta-lactam TDM is not well established. TDM also requires the availability of specific infrastructure, knowledge and expertise. Observational studies and systematic reviews have demonstrated that TDM leads to an improvement in achieving target concentrations, a reduction in potentially toxic concentrations and improvement of clinical and microbiological outcomes. However, a small number of randomized controlled trials have not shown a mortality benefit. Opportunities for improved study design are apparent, as existing studies are limited by their inclusion of heterogeneous patient populations, including patients that may not even have infection, small sample size, variability in the types of beta-lactams included, infections caused by highly susceptible bacteria, and varied sampling, analytical and dosing algorithm methods. Here we review the fundamentals of beta-lactam TDM in critically ill patients, the existing clinical evidence and the practical aspects involved in beta-lactam TDM implementation.

Therapeutic Drug Monitoring of Antibiotics Is Needed in the Treatment of Sepsis

The article presents the results of a prospective on e-c enter observational clinical study. The level of therapeutic drug monitoring antibiotics was studied in patients with sepsis. The objective: to assess the impact of pharmacokinetics and pharmacodynamics parameters of the main classes of antibacterial drugs using specific indices to improve the effectiveness of ongoing antimicrobial therapy in patients with sepsis asscoaited with the infectious process with pa n-r esistant nosocomial microflora. Subjects and Methods. A total of 8 patients with sepsis meetiing the criteria of Sepsi s-3 were included. Carbapenems, oxazolidinones, and aminoglycosides were used in the treatment. Concentrations of drugs in blood plasma were studied by hig h-p erformance liquid chromatography with mass spectrometry. Analysis of the effectiveness of treatment was performed on the third day of therapy. Results. The T > MIC index reached 40% of the time interval between the two administrations for MIC for Pseudomonas aeruginosa in only two cases for group II carbapenems. In both cases, high peak concentrations of the drug (19.5 and 35.4 m g/L , respectively) were observed, a low static volume of antibiotic distribution (0.06 l/k g and 0,09 l/k g) and reduced total clearance of the drug (7.18 and 4.11 m l/h r) were noted. The peak concentration of amikacin was low (3.35 m g/l ), while the time to achieve it and the level of static volume distribution (356.5 liters) increased. The peak concentration of linezolid was reduced in all observations and amounted to 4.04 and 3.35 m g/l . The time of its achievement was increased (3.27 and 6.6 hours), the ratio of AU C / M IC was low and made 76.8 and 59.2. The resolution of organ dysfunction and reduction of manifestations of infectious intoxication were noted only in three patients on the third day of observation. Conclusion. Static pharmacokineti c/p harmacodynamic criteria may serve as a guideline for antimicrobial therapy. Limitations in changing the tactics of antimicrobial therapy based on the use instruction nevertheless allow optimizing treatment by controlling the volume of distribution of the drug, presence of renal or hepatic insufficiency that, however, does not guarantee treatment success. The volume of therapeutic drug monitoring of antibiotics sufficient for compilation of static pharmakinetic models, does not meet the requirements of modern intensive care.

Impact of therapeutic drug monitoring of antibiotics in the management of infective endocarditis.

Treatment of infective endocarditis (IE) is based on high doses of antibiotics with a prolonged duration. Therapeutic drug monitoring (TDM) allows antibiotic prescription optimization and leads to a personalized medicine, but no study evaluates its interest in the management of IE. We conducted a retrospective, bicentric, descriptive study, from January 2007 to December 2019. We included patients cared for IE, defined according to Duke's criteria, for whom a TDM was requested. Clinical and microbiological data were collected after patients' charts review. We considered a trough or steady-state concentration target of 20 to 50mg/L. We included 322IE episodes, corresponding to 306 patients, with 78.6% (253/326) were considered definite according to Duke's criteria. Native valves were involved in 60.5% (185/306) with aortic valve in 46.6% (150/322) and mitral in 36.3% (117/322). Echocardiography was positive in 76.7% (247/322) of cases. After TDM, a dosage modification was performed in 51.5% (166/322) (decrease in 84.3% (140/166)). After initial dosage, 46.3% (82/177) and 92.8% (52/56) were considered overdosed, when amoxicillin and cloxacillin were used, respectively. The length of hospital stay was higher for patient overdosed (25days versus 20days (p = 0.04)), and altered creatinine clearance was associated with overdosage (p = 0.01). Our study suggests that the use of current guidelines probably leads to unnecessarily high concentrations in most patients. TDM benefits predominate in patients with altered renal function, but probably limit adverse effects related to overdosing in most patients.

Therapeutic Drug Monitoring of Antibiotics in Critically Ill Children: An Observational Study in a Pediatric Intensive Care Unit.

Septic critically ill children are at a high risk of inadequate antibiotic exposure, requiring them to undergo therapeutic drug monitoring (TDM). The aim of this study was to describe the use of TDM for antibiotics in critically ill children. The authors conducted a single-center observational study between June and December 2019, with all children treated with antibiotics in a pediatric intensive care unit located in a French university hospital. Standard clinical and laboratory data were recorded. Blood samples were collected for routine laboratory tests, and plasma antibiotic levels were assayed using validated analytical methods. A total of 209 children received antibiotics. TDM was performed in 58 patients (27.8%) who had a greater mean organ dysfunction (according to the International Pediatric Sepsis Consensus Conference) (3 versus 1 in the non-TDM group; P < 0.05) and were treated with antibiotics for longer. A total of 208 samples were analyzed. The median [interquartile range] assay turnaround time was 3 (1-5) days, and 48 (46.2%) of the 104 initial antibiotic concentration values were below the pharmacokinetic/pharmacodynamic targets. A total of 34 (46%) of the 74 off-target TDM measurements available before the end of the antibiotic treatment prompted dose adjustment. This dose adjustment increased the proportion of on-target TDM measurements (70% versus 20% without adjustment). Subsequent measurements of the minimum inhibitory concentration showed that the use of the European Committee on Antimicrobial Susceptibility Testing's epidemiological cutoff values led to underestimation of pharmacokinetic/pharmacodynamic target attainment in 10 cases (20%). TDM seems to be an effective means of optimizing antibiotic exposure in critically ill children. This requires timely plasma antibiotic assays and minimum inhibitory concentration measurements. It is important to define which patients should undergo TDM and how this monitoring should be managed.

Quantification of Antibiotics in Patient Samples: State of the Art in Standardization and Proficiency Testing.

For many antibiotics, the convenient one-fits-all dosing regimen had to be abandoned. Owing to highly variable pharmacokinetics, therapeutic drug monitoring has become an indispensable prerequisite. It is based on a suitable measuring method, sample materials, and standardization. Appropriate quality control including external quality assessment (EQA) is essential. For many antibiotics, EQAs have been established for many decades, whereas others have only lately been introduced. This article gives an insight into the state of the art regarding the therapeutic drug monitoring of antibiotics regarding standardization, EQAs, and reference measurement procedures (RMPs). An overview of the currently available international EQA schemes for antibiotics and a literature overview of available RMPs are given. EQAs including gentamicin and vancomycin have been offered by German providers for more than 25 years. The period 2000-2020 was selected for a detailed analysis. The experiences with a new EQA including linezolid, meropenem, and piperacillin are described. EQAs for gentamicin and vancomycin are provided in many countries. Those for linezolid, meropenem, and piperacillin do not seem to be very common. Most of the antibiotics monitored for decades are measured by commercially available assays. EQAs for linezolid, meropenem, and piperacillin introduced in 2018 were rapidly accepted in Germany. Methods reported in this study were HPLC based either with UV or mass spectrometric detection. The number of participants succeeding was comparable between UV and mass spectrometry. Candidate RMPs for gentamicin, vancomycin, and linezolid based on isotope dilution mass spectrometry were published. EQAs are offered regularly for many antibiotics worldwide. The results of EQAs in Germany generally compare well, but there is potential for improvement. Both immunoassays and HPLC-based methods work properly in EQAs evaluated in Germany. From a quality control perspective, fast and inexpensive methods may be selected without endangering the patient's health based on clinical needs.

Therapeutic Drug Monitoring of Antibiotics in the Elderly: A Narrative Review.

Antibiotic dosing adaptation in elderly patients is frequently complicated by age-related changes affecting the processes of drug absorption, distribution, metabolism, and/or elimination. These events eventually result in treatment failure and/or development of drug-related toxicity. Therapeutic drug monitoring (TDM) can prevent suboptimal antibiotic exposure in adult patients regardless of age. However, little data are available concerning the specific role of TDM in the elderly patients. This review is based on a PubMed search of the literature published in the English language. The search involved TDM studies of antibiotics in the elderly patients performed between 1990 and 2021. Additional studies were identified from the reference lists of the retrieved articles. Studies dealing with population pharmacokinetic modeling were not considered. Only a few studies, mainly retrospective and with observational design, have specifically dealt with appropriate antibiotic dosing in the elderly patients based on TDM. Nevertheless, some clinical situations in which the selection of optimal antibiotic dosing in the elderly patients was successfully guided by TDM were identified. Elderly patients are at an increased risk of bacterial infections and inadequate drug dosing compared with younger patients. Therefore, the availability of TDM services can improve the appropriateness of antibiotic prescriptions in this population.

Therapeutic Drug Monitoring of Antibiotics in Critically Ill Patients: Current Practice and Future Perspectives With a Focus on Clinical Outcome.

Early initiation of antibiotics is essential for ameliorating infections in critically ill patients. The correct dosage of antibiotics is imperative to ensure their adequate exposure. Critically ill patients have altered pharmacokinetic parameters and are often infected by less susceptible microorganisms. Differences in drug disposition are not considered with standard doses of antibiotics. This can lead to suboptimal antibiotic exposure in critically ill patients. To overcome this problem of suboptimal dosing, therapeutic drug monitoring (TDM) is a strategy commonly used to support individualized dosing of antibiotics. It is routinely used for vancomycin and aminoglycosides in clinical practice. In recent years, it has become apparent that TDM may also be used in other antibiotics. This review summarizes the evidence for TDM of antibiotics in critically ill patients, focuses on clinical outcomes, and summarizes possibilities for optimized TDM in the future. After reviewing the literature, we can conclude that general TDM implementation is advised for glycopeptides and aminoglycosides, as evidence of the relationship between TDM and clinical outcome is present. For antibiotics, such as beta-lactams, fluoroquinolones, and linezolid, it seems rational to perform TDM in specific patient cases. TDM involving other antibiotics is supported by individual cases, specifically to decrease toxicity. When focusing on future possibilities to improve TDM of antibiotics in critically ill patients, implementation of model-informed precision dosing should be investigated because it can potentially streamline the TDM process. The logistics of TDM, such as turnaround time and available equipment, are challenging but may be overcome by rapid bioanalytical techniques or real-time monitoring of drug concentrations through biosensors in the future. Education, clinical information on targets, and clinical outcome studies are other important factors that facilitate TDM implementation.

Quantification of 15 Antibiotics Widely Used in the Critical Care Unit with a LC-MS/MS System: An Easy Method to Perform a Daily Therapeutic Drug Monitoring.

Potential under- or overdose of antibiotics may occur in intensive care units due to high variability in plasma concentrations. The risk is either treatment failure or toxicity. Thus, therapeutic drug monitoring of antibiotics may guide dosing adjustment, maximising antibacterial efficacy and minimising toxicity. The aim of this study was to develop and validate a method for the analysis of 15 antibiotics including beta-lactams, linezolid, fluoroquinolones, daptomycin, and clindamycin to have a complete panel in the management of infections. We proposed to develop a fast, sensitive, and quantitative method for the analysis of 15 antibiotics using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometer (UPLC-MS/MS) technology. this method required only 100 µL of plasma and consisted of a rapid liquid–liquid deproteinisation using methanol. Calibration curves ranged from 0.078 to 500 mg/L depending on the molecules, and were defined according to a therapeutic range. Inter- and intra-assay precisions values were less than 15%. This work described the development and the full validation of a precise, sensitive and accurate assay using UPLC-MS/MS technology. After validation, this new assay was successfully applied to routine therapeutic drug monitoring.

Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study

BackgroundEffective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO.MethodsBetween October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints.ResultsThe final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem.ConclusionsECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.

The ONTAI study - a survey on antimicrobial dosing and the practice of therapeutic drug monitoring in German intensive care units.

Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays. Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire. The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly. German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking.

Appropriate therapeutic drug monitoring of antibiotics contributed to lower nephrotoxicity .

The main objective of this study was to evaluate therapeutic drug monitoring (TDM) services for antibiotics and investigate the association between non-adherence to TDM guidelines and development of nephrotoxicity. This retrospective study was conducted using electronic health records of hospitalized patients who received antibiotics for which TDM was requested over a 1-year period. Adherence to TDM guidelines was measured by reviewing appropriate indications, sampling times, result reporting, and clinical pharmacist interventions. A total of 1,179 patients (65% males), for whom TDM was requested during 2017 were included. Upon an assessment of the appropriateness of sampling times, we found that ~15% of samples were drawn at the wrong time, and in over 46% of the cases, TDM service was inconsistent with guidelines. Further, although physicians accepted the majority of pharmacists' interventions related to the TDM service, the pharmacist did not provide any recommendation in more than one-third of the cases. Nephrotoxicity was the most common adverse reaction and was observed in 19.5% of the patients. Furthermore, we found a significant correlation between nephrotoxicity and non-adherence to TDM guidelines (OR = 1.47; p = 0.014). Our study shows that adherence to the guidelines and implementation of an appropriate and effective TDM service for antibiotics increases the number of patients with adequate plasma levels, optimizes clinical outcomes, and minimizes toxicities. Moreover, there was a strong association between non-adherence to the TDM guidelines and development of nephrotoxicity. The findings suggest that adherence to TDM guidelines not only improves clinical practice but also contributes to the reduction of the cost associated with the development of nephrotoxicity.

Simultaneous Determination of Cefalexin, Cefazolin, Flucloxacillin, and Probenecid by Liquid Chromatography-Tandem Mass Spectrometry for Total and Unbound Concentrations in Human Plasma.

Pharmacokinetic studies and therapeutic drug monitoring of antibiotics require a simple, rapid, and reliable analytical method for monitoring the concentrations in plasma, including unbound concentrations for highly protein-bound drugs. The aim of the current work was to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound concentrations of 3 widely used β-lactam antibiotics (cefalexin, cefazolin, and flucloxacillin) and the often coadministered drug probenecid in human plasma, suitable for pharmacokinetic studies and for routine use in ordinary, busy hospital laboratories. Unbound drug was separated from bound drug by ultrafiltration. A simple 1-step protein precipitation was used for sample preparation. Cefalexin, cefazolin, flucloxacillin, probenecid, and their corresponding isotopically labeled internal standards were then resolved on a C18 (2) column. All the compounds were detected using electrospray ionization in the positive mode. Standard curves were linear for all compounds over the concentration range of 0.2-100 mg/L (r > 0.99) for total drug in plasma and 0.01-10 mg/L (r > 0.99) for unbound drug in plasma ultrafiltrate. For both total and unbound drugs, bias was <±10%, and intra- and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 0.2 mg/L for total plasma concentrations and 0.01 mg/L for plasma ultrafiltrate concentrations of all drugs. The method has proven to be simple, rapid, robust, and reliable and is currently being used in clinical pharmacokinetic studies and in the routine clinical service to enhance the effective use of the β-lactam antibiotics.

Multiplex Therapeutic Drug Monitoring by Isotope-dilution HPLC-MS/MS of Antibiotics in Critical Illnesses.

There is an ever-increasing demand for the therapeutic drug monitoring of antibiotics in many clinical facilities, particularly with regard to the implementation of hospital antibiotic stewardship programs. In the current work, we present a multiplex high-performance liquid chromatography-tandem mass spectrometry (HPCL-MS/MS) protocol for the quantification of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid, and piperacillin, commonly used antibiotics in intensive care units. The method was previously comprehensively validated according to the guideline of the European Medicines Agency. After a rapid sample cleanup, the analytes are separated on a C8 reverse-phase HPLC column within 4 minutes and quantified with the corresponding stable isotope-labeled internal standards in electrospray ionization (ESI+) mass spectrometry in multiple reaction time monitoring (MRM). The presented method uses a simple instrumentation setting with uniform chromatographic conditions, allowing for the daily and robust antibiotic therapeutic drug monitoring in clinical laboratories. The calibration curve spans the pharmacokinetic concentration range, thereby including antibiotic amounts close to the minimal inhibitory concentration (MIC) of susceptible bacteria and peak concentrations (Cmax) that are obtained with bolus administration regimens. Without the necessity of the serum dilution before the sample cleanup, the area under the curve for an administered antibiotic can be obtained through multiple measurements.

Impact of β-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy.

The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of β-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). β-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered β-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10× the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of β-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of β-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. β-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive β-lactam concentrations.

The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients.

Cancer remains a leading cause of mortality and morbidity worldwide. In addition to organ failure, the most frequent reasons for admission of cancer patients to intensive care units (ICU) are: infections and sepsis. As critically ill, the complexity of the health situation of cancer patients renders the standard antimicrobial regimen more complex and even inadequate which results in increased mortality rates. This is due to pathophysiological changes in the volume of distribution, increased clearance, as well as to organ dysfunction. While in the former cases a decrease in drug efficacy is observed, the hallmark of the latter one is overdosing leading to increased toxicity at the expense of efficacy. Furthermore, an additional risk factor is the potential drug-drug interaction between antibiotics and antineoplastic agents. Therefore, therapeutic drug monitoring (TDM) is a necessity to improve the clinical outcome of antimicrobial therapy in cancer patients. To be applied in routine analysis the method used for TDM should be cheap, fast and highly accurate/sensitive. Furthermore, as ICU patients are treated with a cocktail of antibiotics the method has to cover the simultaneous analysis of antibiotics used as a first/second line of treatment. The aim of the current review is to briefly survey the pitfalls in the current antimicrobial therapy and the central role of TDM in dose adjustment and drug-drug interaction's evaluation. A major section is dedicated to summarize the currently published analytical methods and to shed light on the difficulties and potential problems that can be encountered during method development.

Assays for determination of ertapenem for applications in therapeutic drug monitoring, pharmacokinetics and sample stability.

Carbapanems are a class of β-lactam antibiotics with broad-spectrum potency and high β-lactamase resistance. Ertapenem, a member of this class, sold under the trade name Invanz™, has been of interest in the world of antibiotic therapeutic drug monitoring owing to its highly standardized 1 g dose and its high degree of plasma protein binding. Owing to the relative newness of this drug, fewer than 30 methods for ertapenem quantification have been published. Among these about half utilize biological matrices at the sample type. Liquid-liquid extraction and protein precipitation prevail as the most frequently used sample preparation techniques, despite their low recoveries compared with solid-phase extraction. Additionally, high-performance liquid chromatography with ultraviolet detection (HPLC-UV) is the instrumentation choice for most ertapenem assays. While these approaches may not achieve the highest possible sensitivity for ertapenem quantification, they provide clinically relevant tools for monitoring ertapenem in real patients. Sample stability is an ongoing concern for laboratories that handle ertapenem analysis, with buffering being of paramount importance, as well as low temperature (<-70°C) storage, to ensure minimal drug degradation in situ.

Suitability of Becton Dickinson Vacutainer rapid serum tube for collecting and storing blood samples for antibiotic and anticonvulsant drug monitoring

AimsTo investigate the suitability of newly developed Becton Dickinson Vacutainer rapid serum tube (RST) for therapeutic drug monitoring of antibiotics and anticonvulsants.MethodsTwo pools of citrated whole blood were created by...